Meredith Stevers

For my thesis work, I am investigating how the sequence of the human U2 snRNA, a non-coding RNA, controls pre-mRNA splicing efficiency and how cancer mutation alters its activity. I have engineered human cells to carry different U2 snRNA mutations and examined their effects on splicing efficiency of a specific splicing reporter and on expression and splicing outcomes of all genes. My results will add to our mechanistic knowledge of the splicing process and our understanding of the role of spliceosome mutation in cancer progression.

During gene expression, the spliceosome must recognize key sequences within introns before their removal from RNA transcripts. The U2 snRNP, a spliceosome subunit containing the U2 snRNA and several proteins, identifies an intron’s branchpoint sequence. Many diseases, including cancer, are linked to mutations in U2 snRNP, but how these mutations affect branchpoint sequence recognition and contribute to disease progression is unknown. My thesis work seeks to understand how the U2 snRNP recognizes the branchpoint sequence and how this recognition event is altered by cancer mutation. Using human cells, I am investigating how mutations to the U2 snRNP alter U2 snRNP expression, spliceosome efficiency, alternative splicing, and gene expression. My results indicate that cancer-associated mutations of the U2 snRNP change the preference of the spliceosome for different branchpoint sequences and alter spliceosome protein expression and metabolic pathways inside the cell. My results will add to our understanding of human splicing mechanism and help identify new therapeutic targets for splicing diseases.